Disproportionation of aliphatic and aromatic aldehydes through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley reactions

Article abstract of DOI:10.1007/s00706-021-02785-9

Disproportionation of aldehydes through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley reactions often requires the application of high temperatures, equimolar or excess quantities of strong bases, and is mostly limited to the aldehydes with no CH₂ or CH₃ adjacent to the carbonyl group. Herein, we developed an efficient, mild, and multifunctional catalytic system consisting AlCl₃/Et₃N in CH₂Cl₂, that can selectively convert a wide range of not only aliphatic, but also aromatic aldehydes to the corresponding alcohols, acids, and dimerized esters at room temperature, and in high yields, without formation of the side products that are generally observed. We have also shown that higher AlCl₃ content favors the reaction towards Cannizzaro reaction, yet lower content favors Tishchenko reaction. Moreover, the presence of hydride donor alcohols in the reaction mixture completely directs the reaction towards the Meerwein–Ponndorf–Verley reaction. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-021-02785-9

Monatshefte für Chemie - Chemical Monthly (2021) 152:803–808
https://doi.org/10.1007/s00706-021-02785-9
ORIGINAL PAPER
Disproportionation of aliphatic and aromatic aldehydes
through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley
reactions
Sina Sharif1,2 · Hannah Sharif2 · Darrell Koza3 · Ali Aminkhani4
Received: 9 March 2020 / Accepted: 17 May 2021 / Published online: 9 July 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
Disproportionation of aldehydes through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley reactions often requires
the application of high temperatures, equimolar or excess quantities of strong bases, and is mostly limited to the aldehydes
with no CH2 or CH3 adjacent to the carbonyl group. Herein, we developed an efcient, mild, and multifunctional catalytic
system consisting AlCl3/Et3N in CH2Cl2, that can selectively convert a wide range of not only aliphatic, but also aromatic
aldehydes to the corresponding alcohols, acids, and dimerized esters at room temperature, and in high yields, without for-
mation of the side products that are generally observed. We have also shown that higher AlCl3 content favors the reaction
towards Cannizzaro reaction, yet lower content favors Tishchenko reaction. Moreover, the presence of hydride donor alcohols
in the reaction mixture completely directs the reaction towards the Meerwein–Ponndorf–Verley reaction.
Graphic abstract
Keywords Cannizzaro · Tishchenko · Meerwein–Ponndorf–Verley · Disproportionation · Aldehyde
Introduction
The Cannizzaro reaction is one of the oldest processes in
synthetic organic chemistry, involving the base-induced
* Sina Sharif
simultaneous oxidation–reduction of aldehydes into their
rsharif@fas.harvard.edu
corresponding alcohols and carboxylic acids. The origi-
1
nal Cannizzaro reaction was carried out in the presence
of equimolar or excess quantities of hydroxides or other
strong bases and was limited to the aldehydes, which lack
α-hydrogens [1]. This is due to the fact that the α-hydrogens
of aliphatic aldehydes are acidic, and in the presence of
strong base they can be removed to form an enolate, which
can subsequently attack to the carbonyl group of another
aldehyde to yield aldol products [2, 3]. Tishchenko reaction
Department of Chemistry, University of Connecticut, Storrs,
CT 06269, USA
2
Disruptive Technology Laboratory, Schepens Eye Research
Institute of Massachusetts Eye and Ear, Harvard Medical
School, Boston, MA 02114, USA
3
4
Department of Science, Eastern Connecticut State University,
Willimantic, CT 06226, USA
Department of Chemistry, Khoy Branch, Islamic Azad
University, 58168 Khoy, Iran
Vol.:(0123456789)
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S. Sharif et al.
has also a similar principle, yet the disproportionation prod-
ucts (alcohol and acid) undergo coupling process, which
also has shown to be very challenging for aliphatic alde-
hydes due to harsh reaction conditions such as application
of high temperatures, equimolar or excess of strong bases
(i.e. aluminum alkoxides) [4–6]. Recently developed proto-
cols involve the applications of Lewis acids [7], solid state
[8], organoactinide [9, 10] and lanthanide [11] and imida-
zolin–2–iminato–Cp*thorium(IV) and aluminum [12] com-
plexes, along with thiolate [13], selenide [14], polymeric
ionic solvent [15], and metal catalysis [16], along with the
aldol–Tishchenko reaction of sulfnimines [17] and lithium
enolates [18]. Nevertheless, the disproportionation reaction
of the aliphatic aldehyde, especially the ones with CH2 or
CH3 adjacent to the carbonyl group are still elusive [3]. Dis-
proportionation reaction of aldehydes, lacking α-hydrogens
in the presence of Lewis acid (i.e. MgBr2 and LiBr) and
triethylamine (Et3N) at room temperature has been previ-
ously reported [19, 20]. Despite ofering mild conditions,
those catalytic systems were still unable to disproportionate
aliphatic aldehyde and preferentially give aldol products [2,
21]. Herein, we described a new catalytic system, which
enables to selectively convert not only aliphatic, but also
aromatic aldehydes to the corresponding alcohols, acids, and
esters at room temperature (Scheme 1).
We initially explored the disproportionation reaction of
benzaldehyde as a model aldehyde. Using catalytic amount
of AlCl3 (Table 1, entry 3) and 0.5 equivalent of Et3N, we
obtained 76% conversion of benzaldehyde to the respective
alcohol/acid and ester. As the reaction mixture had a high
viscosity, we reasoned that the addition of solvent could
improve molecular collisions and consequently the conver-
sion degree. Our results indicated that the conversion degree
of the reaction is the highest for nonpolar solvent (CH2Cl2).
Moreover, we tuned the concentration of the AlCl3 in the
reaction from 1:1 (Table 1, entry 7) to 1:100 (Table 1, entry
13) for RCHO: AlCl3 ratio. We witnessed that the while
the catalytic amount of Lewis acid leads to ester product
(Tishchenko reaction), the higher amount favors the forma-
tion of corresponding alcohol and acid (Cannizzaro reaction)
as shown in Table 1. We theorized that the AlCl3 in a high
concentration can coordinate two aldehydes, followed by
nucleophilic attack of Et3N to form a complex, and con-
sequent conversion of those aldehydes to an alcohol and
acid products upon aqueous workup. However, if used in
a catalytic amount, AlCl3 frst can form the complex, and
induce the hydride shift, then coordinate two other alde-
hydes and form new complex while dissociating from the
frst set (Scheme 2).
Such migration of AlCl3 drives the nucleophilic attack
of the alcohol to the unstable amide and leads to coupling
Results and discussion
Table 1 Optimization of Cannizzaro/Tishchenko reaction
Exposing aliphatic aldehyde, in particular, the ones with
CH2 or CH3 adjacent to the carbonyl group to dispropor-
tionation reaction conditions preferentially leads to the for-
mation of aldol products. This is due to the fact that the
α-hydrogens of aliphatic aldehydes are acidic, and in the
presence of strong base they can be removed to form an eno-
late, which can subsequently attack to the carbonyl group of
another aldehyde to yield aldol products [2, 3]. Inspired by
the original Tishchenko reaction of using Al(OR)3 catalyst,
and previously developed protocol of the Lewis acid/Et3N
system, we envisioned that the AlCl3/Et3N system could be
utilized to perform such transformation.
Entry
n
Solvent
Et3N/eq
Ca: T/%
Yield/%b
1
2
3
4
5
6
7
8
0.05
0.05
0.05
0.05
0.05
0.05
1
0.5
0.2
0.1
CH3CN
CH3CN
–
0.5
0.1
0.5
0.1
1
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4:45
2:19
7:69
4:39
6:85
4:47
89:6
87:9
83:14
73:24
5:93
3:96
1:97
48
21
76
43
91
51
95
96
97
97
98
99
98
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
13
0.05
0.02
0.01
aThe reaction yields were almost similar for alcohol and carboxylic
acids products in the Cannizzaro reaction
bMeasured by 1H NMR analysis of the crude
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Disproportionation of aliphatic and aromatic aldehydes through Cannizzaro, Tishchenko,…
805
solvent (Table 1, entries 3, 4), yet with comparatively lower
yield. This may originate from higher viscosity of the reac-
tion mixture in the absent of solvent, which can lower the
chance of molecular collision and subsequently reduce the
reaction yield. To better understand the reaction mechanism,
we monitored the reaction progress as a function of time
for the varying concentrations of AlCl3 as shown in Fig. 1.
Initially, the conversion rate was greater for the reactions
with higher concentrations of AlCl3, favoring Cannizzaro
reaction products (Fig. 1a, c). However, as the reaction pro-
gresses, the reaction with lower AlCl3 concentration, super-
sede the ones with the higher content, and preferentially led
to Tishchenko reaction products (Fig. 1b, c). This suggests
that the formation of Al complex and the migration of AlCl3
from one complex to a new set of aldehydes are fast. In addi-
tion, the higher viscosity of the mixture in the reactions with
greater AlCl3 content may decline the chance of molecular
collision and reduce the reaction rate.
products. Moreover, while 0.5 equivalent of Et3N is neces-
sary for the reaction completion, the presence of an excess
amount reduces the reaction rate and subsequently yield
(Table 1, entry 5), possibly due to the fact that the excess
Et3N can complete more efectively for the Lewis acid and
consequently lower the conversion yield.
Moreover, the disproportionation reaction has shown to
present a higher yield in nonpolar CH2Cl2 solvent, compared
to polar CH3CN. This is highly likely due to complexation
of N of CH3CN by the Lewis acid, along with altering the
free energy of the species in the polar media, requiring more
activation energy for the reactants to reach the transition
state apex. The reaction also can progress in the absent of
To realize the versatility of the reaction, we next sub-
jected a variety of aldehydes to our disproportionation
conditions. Both electron-rich (Table 2, entries 1, 2, 6, and
Fig. 1 Disproportionation of
a
b
benzaldehyde through Canniz-
zaro a and Tishchenko reactions
b in the presence Et3N and var-
ying amount of AlCl3 catalyst as
a function of time. c The overall
conversion rate for dispropor-
tionation of benzaldehyde
Reaction time / h
Reaction time / h
c
Reaction time / h
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806
S. Sharif et al.
Table 2 Switching Cannizzaro/Tishchenko reactions of aromatic and aliphatic aldehydes in the presence of AlCl3/Et3N
Yield
/% b
86
Yield
Entry R
1
n
1
C a : T /%
78 : 8
Entry R
9
n
1
C a : T /%
52 : 5
/% b
57
0.05 9 : 82
72 : 12
0.05 8 : 79
80 : 10
0.05 3 : 88
91 : 1
0.05 87 : 7
87 : 5
0.05 11 : 79
74 : 12
0.05 9 : 81
77 : 7
0.05 7 : 81
75 : 8
0.05 3 : 77
90
0.05 7 : 65
57 : 6
0.05 7 : 63
81 : 7
0.05 5 : 80
65 : 6
0.05 7 : 67
86 : 6
0.05 7 : 88
82 : 6
0.05 7 : 84
73 : 6
0.05 8 : 74
72
63
1
84
87
90
1
2
10
70
88
1
1
3
4
5
11
12
13
91
92
94
92
90
85
79
81
92
95
1
1
1
1
1
86
1
88
6
7
8
14
15
90
84
88
83
91
72
70
OMe
1
1
1
80
aThe reaction yields were similar for alcohol and carboxylic acids products in the Cannizzaro reaction
bYields of isolated products characterized by 1H NMR
7), electron-poor (entries 3–6) functionalized derivatives
of benzaldehyde along with heterocyclic systems (entries
8–10), all underwent disproportionation reaction and gave
excellent yields of conversion to corresponding esters or
alcohol and acids, depending on the reaction conditions. Our
data indicated that the substrates bearing electron-defcient
aryl moieties gave a comparatively higher yield than those
with electron-donating groups and heterocyclic aldehydes at
room temperature. This is consistent with previous studies,
suggesting that the hydride shift is still the rate determining
step of the reaction [19]. However, we did not observe any
correlation between the position of substituents (i.e. ortho
vs. para) on the benzene ring and the reaction yield or direc-
tion towards Cannizzaro or Tishchenko products. Next, we
probed whether aliphatic aldehydes would be amenable to
disproportionation reaction. We were delighted to fnd the
not only straight-chain systems (entries 11–14), but also the
branched aliphatic aldehydes (entry 15) can also undergo
Cannizzaro and Tishchenko reactions in good yields, with-
out the formation of common aldol products. However, the
conversion degree for both reactions was comparatively
lower than those with the aryl moieties, due to their elec-
tron donating natures. To improve the reaction yield and
time, we increased the AlCl3 content to 0.2 equiv. How-
ever, while the aldehyde was completely consumed within
15 h, we witnessed the formation of isopropyl benzoate
product, suggesting the disproportionation reaction (Can-
nizzaro or Tishchenko reactions) is competing with Meer-
wein–Ponndorf–Verley (MPV) reduction. On the other hand,
elongating reaction time to 2 days improved the reaction
yield to 92%.
To study the adaptability of the reaction condition, we
also subjected a variety of aromatic and aliphatic aldehydes
to adopted MPV reaction (Table 3). Our data showed that
both electron-rich (Table 3, entries 1 and 2), electron-poor
(entries 3–6) functionalized derivatives of benzaldehyde and
heterocyclic systems (entries 6 and 7) along with aliphatic
1 3

Disproportionation of aliphatic and aromatic aldehydes through Cannizzaro, Tishchenko,…
807
Table 3 MPV reactions of aldehydes in the presence of AlCl3/Et3N
Experimental
All chemicals were purchased from Sigma-Aldrich. The
aldehydes were distilled with bubble distillation and
kept under inert atmosphere (argon) prior to the reac-
tions. The CH2Cl2 was treated with CaH2 overnight and
distilled prior to addition to the reaction. Anhydrous
AlCl3 (> 99%) and trimethylamine (> 99.5%) were used
as purchased without any further purification yet under
EntryR
1
Yield /%a Entry R
Yield /%a
88
78
75
81
82
92
9
1
argon atmosphere. H NMR spectra were recorded on
68
74
79
82
2
3
4
5
10
11
12
13
Bruker DMX 500 MHz NMR spectrometer using tetra-
methylsilane (TMS) as an internal standard. GC–MS
analysis was performed on Agilent 6890 (GC)/5972A
(MS). Melting point measurements were performed on
Fisherbrand™ Digital Melting Point apparatus, and
boing points was assessed with standard distillation
method.
73
81
6
14
OMe
General experimental methods for AlCl3‑catalyzed
Cannizzaro/Tishchenko reactions
79
91
83
72
7
8
15
16
A mixture of AlCl3 (0.5 mmol), the aldehyde (10 mmol),
and triethylamine (5 mmol) was added to 2 cm3 of dried
CH2Cl2 and stirred for 2 days at room temperature under
argon atmosphere until the aldehyde was completely
consumed. The reaction progress was probed by TLC
and GC/MS (Agilent 6890 (GC)/5972A (MS)). The reac-
tion mixture was then filtered through Whatman filter
paper (grade 2), and treated with sodium bicarbonate
solution, followed by isolating the organic phase via a
separatory funnel. The aqueous phase washed several
times with CH2Cl2 to make sure that all organic materi-
als extracted. Then, the organic phase was dried using
sodium sulfate and subsequently analyzed by GC/MS
F
aYields of isolated alcohols characterized by 1H NMR
aldehydes (entries 8–12) all underwent MPV reaction with
high yields of conversion. This indicates that the AlCl3/Et3N
is a mild and versatile catalytic system for disproportionation
of both aliphatic and aromatic aldehydes into alcohol, acid,
and ester products.
1
Conclusion
and H NMR, and validated using melting or boiling
point of the product.
We have shown that AlCl3/Et3N is an efcient and mild
catalytic system to selectively convert the aliphatic and
aromatic aldehydes to the corresponding alcohols, acids,
and esters through Cannizzaro, Tishchenko, and MPV
reactions at room temperature. This system not only has
the advantage of using very inexpensive reactants, in very
mild conditions, which are crucial for large-scale synthe-
sis, but also afords the desired products with very high
yields without formation of the side products that are gen-
erally detected under other conditions. The application of
the AlCl3/Et3N for asymmetric disproportionation of the
aldehydes into esters and alcohol/acids are currently being
investigated to extend the versatility of the present system
and expected to ofer a better mechanistic understanding
of this transformation.
General experimental methods for AlCl3 catalyzed
Meerwein–Ponndorf–Verley (MPV) reactions
A mixture of AlCl3 (0.1–10 mmol), the aldehyde (10 mmol),
triethylamine (10 mmol) and isopropanol (10 mmol) was
added to 2 cm3 of dried CH2Cl2 and stirred for 2 days at
room temperature under argon atmosphere until the alde-
hyde was completely consumed. The reaction progress was
monitored by TLC and GC/MS. The reaction mixture was
then fltered, and treated with sodium bicarbonate solution,
followed by isolating the organic phase via a separatory fun-
nel. The aqueous phase washed several times with CH2Cl2 to
ensure that all organic materials extracted. Then, the organic
phase was dried over sodium sulfate, and subsequently ana-
lyzed by GC/MS and 1H NMR and validated using melting
or boiling point of the product.
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S. Sharif et al.
Acknowledgements We are grateful to the fnancial support from
Isolation of the components
Boston-KPro research fund.
To isolate the products of the reactions, frst the reaction
mixture was fltered and then treated with NaH2PO4 solu-
tion. Nest, the organic phase was separated via a separa-
tory funnel, and the aqueous phase washed several times
with CH2Cl2 to ensure that all organic materials were
extracted. Afterward, the organic phase was dried over
sodium sulfate. The reaction components of aromatic reac-
tants (Table 2: entry 1–10 and Table 3: entry 1–11) were
separated via fash column chromatography over silica gel
60 (0.040–0.063 mm; 230–400 mesh ASTM). The starting
mobile phase was hexane:ethylacetate (4:1) to elute and
separate aldehydes, alcohols, and esters, followed by the sec-
ond mobile phase solution (ethyl acetate:methanol (10:1))
to elute the carboxylic acids. The reaction components of
aliphatic reactants (Table 2: entry 11–15 and Table 3: entry
12–16) were separated via bulb to bulb distillation.
References
1. Geissman TA (2011) The Cannizzaro Reaction: Organic reactions,
John Wiley & Sons, Inc,. Hoboken, NJ, p 94. https://doi.org/10.
1002/0471264180.or002.03
2. Abaee MS, Mojtahedi MM, Zahedi MM, Sharif R (2007) Heter-
oat Chem 18:44
3. Mahrwald R (2009) Aldol reactions. Springer, Netherlands
4. Lin I, Day AR (1952) J Am Chem Soc 74:5133
5. Morita K, Nishiyama Y, Ishii Y (1993) Organometallics 12:3748
6. Takashi I, Hiroshi H, Yoshitaka K, Akio Y (1982) Bull Chem Soc
Jpn 55:504
7. Crimmin MR, Barrett AGM, Hill MS, Procopiou PA (2007) Org
Lett 9:331
8. Seki T, Hattori H (2003) Catal Surv Asia 7:145
9. Liu H, Khononov M, Fridman N, Tamm M, Eisen MS (2018) J
Organomet Chem 857:123
10. Karmel ISR, Fridman N, Tamm M, Eisen MS (2014) J Am Chem
Soc 136:17180
Reaction rate study
11. Zuyls A, Roesky PW, Deacon GB, Konstas K, Junk PC (2008)
Eur J Org Chem 2008:693
12. Guo Z, Wang S, Wei X (2016) J Organomet Chem 818:115
13. Curran SP, Connon SJ (2012) Angew Chem Int Ed 51:10866
14. Curran SP, Connon SJ (2012) Org Lett 14:1074
15. Daemi H, Barikani M, Jahani M (2016) New J Chem 40:2121
16. Hoshimoto Y, Ohashi M, Ogoshi S (2011) J Am Chem Soc
133:4668
To study the Cannizzaro/Tishchenko reaction rate, we made
a series of reaction mixtures of benzaldehyde (100 mmol),
and triethylamine (50 mmol) in 20 cm3 of dried CH2Cl2
along with varying amount of AlCl3 (i.e. 2, 5, 10, 20, 50,
and 100 mmol). The reaction mixtures were stirred at room
temperature under argon atmosphere, and 2 cm3 of each
reaction mixture was removed at each time points (i.e. 1, 2,
4, 8, 16, 24, and 48 h) from the fask, followed by fltration
and washing with sodium bicarbonate. The resultant samples
were dried over sodium sulfate and analyzed using GC/MS.
The reaction rate study was triplicated and the conversion
degree for each reaction mixture was calculated from the
average concentration the products in the reaction mixtures,
using GC/MS spectra.
17. Foley VM, McSweeney CM, Eccles KS, Lawrence SE,
McGlacken GP (2015) Org Lett 17:5642
18. Bodnar PM, Shaw JT, Woerpel KA (1997) J Org Chem 62:5674
19. Abaee MS, Sharif R, Mojtahedi MM (2005) Org Lett 7:5893
20. Mojtahedi MM, Akbarzadeh E, Sharif R, Abaee MS (2007) Org
Lett 9:2791
21. Abaee MS, Mojtahedi MM, Zahedi MM, Sharif R, Khavasi H
(2007) Synthesis 21:3339
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1 3